Limited regions of the α2-domain α-helix control anti-A2 allorecognition: an analysis using a panel of A2 mutants

Giovanna Lombardi, Masanori Matsui, Robert Moots, Gerald Aichinger, Sid Sidhu, Richard Batchelor, Jeff Frelinger, Robert Lechler

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

The regions of the HLA-A2 molecule controlling anti-A2 alloreactivity were explored using naturally occurring allelic variants of HLA-A, and a panel of transfectants expressing the products of A2.1 genes that had been mutated at multiple positions encoding residues in the α2 domain α-helix. As a means of detecting distant conformational effects, these altered A2.1 molecules were also examined serologically. Amino acid substitutions at the carboxy-terminal end of the α2 domain α-helix led to diminished staining with the monoclonal antibody (mAb) MA2.1. The epitope for this antibody has previously been mapped to the α1 domain α-helix (residues 62-65). This suggests that interdomain contacts may cause conformational alteration, and that mutants can have distant, as well as local effects. Of the 24 positions where substitutions were made, only six led to loss of the anti-A2 alloresponse by the three clones and three lines that were tested. In addition, the mutations that altered the MA2.1 epitope, located on the α1 domain α-helix, did not inhibit allorecognition. This suggests that a limited number of regions on the A2.1 molecule are responsible for allodeterminant expression. The most influential substitutions were those at positions 152, 154, 162, and 166. It is notable that three of these are predicted to be T-cell receptor (Tcr)-contacting residues, and one (152) to contribute to peptide binding. These results suggest that the specificity of alloreactive T cells is determined by exposed polymorphisms, directly contacted by the Tcr, and by concealed polymorphisms which influence peptide binding.

Original languageEnglish (US)
Pages (from-to)149-156
Number of pages8
JournalImmunogenetics
Volume34
Issue number3
DOIs
StatePublished - Sep 1 1991
Externally publishedYes

ASJC Scopus subject areas

  • Immunology
  • Genetics

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    Lombardi, G., Matsui, M., Moots, R., Aichinger, G., Sidhu, S., Batchelor, R., Frelinger, J., & Lechler, R. (1991). Limited regions of the α2-domain α-helix control anti-A2 allorecognition: an analysis using a panel of A2 mutants. Immunogenetics, 34(3), 149-156. https://doi.org/10.1007/BF00205817